Oligosyndactyly (Os) is a semidominant mutation located on chromosome 8 of the mouse. In heterozygous form, Os results in syndactyly, diabetes insipidus (due to a reduction in size of te kidney) and muscular anomalies. When homozygous, the gene is lethal very early during development. In homozygous embryos, large numbers of cells accumulate in metaphase at the blasocyst stage and the embryos die shortly after this. No evidence has been yet obtained which links the effects found in heterozygous mice with embryonic lethality that occurs in homozygous embryos. It is my belief that determining the cause of lethality will allow one to understand the basis of the heterozygous defects. My working hypothesis is that the Os gene in homozygous embryos results in either abnormal spindle formation or blocked chromosome movement. Therefore, the experiments outlined in this proposal are aimed at determining if such defects exist. A unique aspect of this proposal is that mutant embruos can be distinguished from normal litermates in segregating litters. Spindle formation will be examined in great detail by microscopic and biochemical techniques. Tubulin synthesis along with microtubule formation and distribution in mutant cells will be examined. Also, the tubulin genes will be mapped to mouse chromosomes using molecular and somatic cell techniques. Finally, if no spindle defect is detected, those factors involved in anaphase chromosome movement will be examined. IN heterozygous mice, a histological examination of affected tissues will be done. Following these studies, experiments will be undertaken to define the basis of the defects in heterozygous mice. These experiments will rely on information obtained from the studies on homozygous embryos. One of the most common congenital limb malformations in man is syndactyly. The defectr resulting in syndactyly in man and other animlas as well is not understood and, in general, is not amenable to study. Studies of syndactyly in mice may ultimately lead to advancement of our understanding of these human malformation states.